New isoquinoline compounds

ABSTRACT

The invention relatests compound of formula (I):  
                 
 
     wherein:  
     n is 1, 2 or 3,  
     A represents a group  
                 
 
     X represents N or NR 1 ,  
     R 2  represents an alkoxy, cycloalkyloxy or cycloalkylalkyloxy group.  
     and medicinal products containing the same which are useful in treading or in preventing melatoninergic disorder.

FIELD OF THE INVENTION

[0001] The present invention relates to new isoquinoline compounds, to aprocess for their preparation and to pharmaceutical compositionscontaining them.

[0002] The compounds of the present invention are, in view of theiroriginal structure, new and have pharmacological properties that are ofgreat interest in relation to melatoninergic receptors.

DESCRIPTION OF THE PRIOR ART

[0003] There are known from the literature isoquinoline compounds thatare useful as vasodilators (U.S. Pat. No. 4,880,817, U.S. Pat. No.4,843,071, U.S. Pat. No. 4,822,800), or useful in the growth of plants(Czasopismo Techniezne (Krakow), 1992, 89 (1), 7-12), as tyrosinephosphatase modulators (WO 99 46268), or also useful in synthesis(Tetrahedron Letters, 2002, 43 (19), 3557-3560; Heterocycles, 2000, 52(3), 1371-1383).

BACKGROUND OF THE INVENTION

[0004] In the last ten years, numerous studies have demonstrated themajor role played by melatonin (N-acetyl-5-methoxytryptamine) in a largenumber of physiopathological phenomena and in the control of thecircadian rhythm, but melatonin has a rather short half-life owing tothe fact that it is rapidly metabolised. Great interest therefore liesin the possibility of making available to the clinician melatoninanalogues that are metabolically more stable and have an agonist orantagonist character and of which the therapeutic effect may be expectedto be superior to that of the hormone itself.

[0005] In addition to their beneficial action in respect of circadianrhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleepdisorders (Psychopharmacology, 1990, 100, pp. 222-226), ligands of themelatoninergic system have valuable pharmacological properties inrespect of the central nervous system, especially anxiolytic andantipsychotic properties (Neuropharmacology of Pineal Secretions, 1990,8 (3-4), pp. 264-272), and analgesic properties (Pharmacopsychiat.,1987, 20, pp. 222-223), and also for the treatment of Parkinson'sdisease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer's disease(Brain Research, 1990, 528, pp. 170-174). The compounds have alsodemonstrated activity in relation to certain cancers (Melatonin—ClinicalPerspectives, Oxford University Press, 1988, pp. 164-165), ovulation(Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology,1986, 24, pp. 359-364), and in the treatment of obesity (InternationalJournal of Eating Disorders, 1996, 20 (4), pp. 443-446).

[0006] Those various effects are exerted via the intermediary ofspecific melatonin receptors. Molecular biology studies havedemonstrated the existence of a number of receptor sub-types that arecapable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p.50; WO 97.04094). It has been possible for some of those receptors to belocated and characterised for different species, including mammals. Inorder to be able to understand the physiological functions of thosereceptors better, it is of great advantage to have available selectiveligands. Moreover such compounds, by interacting selectively with one oranother of those receptors, may be excellent medicaments for theclinician in the treatment of pathologies associated with themelatoninergic system, some of which have been mentioned above.

[0007] In addition to being new, the compounds of the present inventionexhibit a very strong affinity for melatonin receptors and/or aselectivity for one or another of the melatoninergic receptor sub-types.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention relates, more especially, to the compoundsof formula

[0009] wherein:

[0010] n is 1, 2or 3,

[0011] A represents a group

[0012] wherein:

[0013] Z represents a sulphur atom or an oxygen atom,

[0014] R and R″, which may be identical or different, each represents ahydrogen atom or a linear or branched (C₁-C₆)alkyl group,

[0015] and R′ represents a linear or branched (C₁-C₆)alkyl group, alinear or branched (C₂-C₆)alkenyl group, a linear or branched(C₂-C₆)alkynyl group, a (C₃-C₈)-cycloalkyl group, a(C₃-C₈)cycloalkyl-(C₁-C₆)alkyl group in which the alkyl moiety is linearor branched, an aryl group, an aryl-(C₁-C₆)alkyl group in which thealkyl moiety is linear or branched, a heteroaryl group or aheteroaryl-(C₁-C₆)alkyl group in which the alkyl moiety is linear orbranched,

[0016] X represents a nitrogen atom or a group N-R¹ wherein R¹represents a hydrogen atom or a linear or branched (C₁-C₆)alkyl group, a(C₃-C₈)cycloalkyl group, a (C₃-C₈)cyclo-alkyl-(C₁-C₆)alkyl group inwhich the alkyl moiety is linear or branched, an aryl group, an aroylgroup, an aryl-(C₁-C₆)alkyl group in which the alkyl moiety is linear orbranched, a heteroaryl group, a heteroaroyl group or aheteroaryl-(C₁-C₆)alkyl group in which the alkyl moiety is linear orbranched,

[0017] R² represents a linear or branched (C₁-C₆)alkoxy group, a(C₃-C₈)cycloalkyloxy or (C₃-C₈)cycloalkyl-(C₁-C₆)alkyloxy group in whichthe alkyloxy moiety is linear or branched,

[0018] the representation

denotes that the bond is single or double, with the proviso that thevalency of the atoms is respected,

[0019] wherein

[0020] “aryl” is to be understood as meaning a phenyl or naphthyl group,those groups being unsubstituted or substituted by from one to threeidentical or different groups selected from linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, OH, COOH, alkoxycarbonylin which the alkoxy moiety is linear or branched, formyl, nitro, cyano,hydroxymethyl, amino (optionally substituted by one or two linear orbranched (C₁-C₆)alkyl groups) and halogen atoms,

[0021] “heteroaryl” is to be understood as meaning any mono- orbi-cyclic group that contains from 5 to 10 ring members and may containfrom 1 to 3 hetero atoms selected from oxygen, sulphur and nitrogen,such as the groups furan, thiophene, pyrrole, imidazoline, pyridine,quinoline, isoquinoline, chroman, indole, benzothiophene or benzofuran,it being possible for those groups to be partially hydrogenated,unsubstituted or substituted by from one to three identical or differentgroups selected from linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)alkoxy, OH, COOH, alkoxycarbonyl in which the alkoxy moiety islinear or branched, formyl, nitro, cyano, amino (optionally substitutedby one or two linear or branched (C₁-C₆)alkyl groups), hydroxymethyl andhalogen atoms,

[0022] to their enantiomers and diastereoisomers, and also to additionsalts thereof with a pharmaceutically acceptable acid or base.

[0023] Among the pharmaceutically acceptable acids there may bementioned, without implying any limitation, hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid,trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinicacid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citricacid, ascorbic acid, methanesulphonic acid, camphoric acid etc.

[0024] Among the pharmaceutically acceptable bases there may bementioned, without implying any limitation, sodium hydroxide, potassiumhydroxide, triethylamine, tert-butylamine etc.

[0025] The preferred values for n are 2 and 3.

[0026] Preferred compounds of the invention are compounds of formula (I)wherein:

[0027] n is 2 and A represents an —NHCOR′ group and more especially an—NHCOR′ group wherein R′ represents a linear or branched (C₁-C₆)alkylgroup, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentylor hexyl for example, or a (C₃-C₈)cycloalkyl group, such as cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl for example,

[0028] n is 3 and A represents a —CONHR′ group and more especially a—CONHR′ group wherein R′ represents a linear or branched (C₁-C₆)alkylgroup, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentylor hexyl for example, or a (C₃-C₈)cycloalkyl group, such as cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl for example.

[0029] The preferred R² group is the alkoxy group and more especiallythe methoxy group.

[0030] X represents preferably a nitrogen atom or an NR¹ group whereinR¹ represents a cycloalkylalkyl group, an unsubstituted or substitutedphenyl group, or a benzyl group in which the phenyl moiety issubstituted or unsubstituted.

[0031] Even more preferably, the invention relates to the followingcompounds of formula (I):

[0032] N-[2-(6-methoxy-4-isoquinolinyl)ethyl]acetamide,

[0033] N-[2-(6-methoxy-4-isoquinolinyl)ethyl]butanamide,

[0034] N-[2-(6-methoxy-4-isoquinolinyl)ethyl]propanamide,

[0035] N-[2-(6-methoxy-4-isoquinolinyl)ethyl]cyclopropanecarboxamide,

[0036] 4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide,

[0037]N-[2-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetamide,

[0038]N-[2-(2-benzyl-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)]ethyl]acetamide,

[0039]N-{2-[2-(cyclopropylmethyl)-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl]-ethyl}acetamide.

[0040] The enantiomers, diastereoisomers and also addition salts with apharmaceutically acceptable acid or base of the preferred compounds ofthe invention form an integral part of the invention.

[0041] The present invention relates also to a process for thepreparation of compounds of formula (I), which process is characterisedin that there is used as starting material a compound of formula (II):

[0042] wherein R² and n are as defined for formula (I) and R_(a)represents a linear or branched (C₁-C₆)alkyl group, which is subjectedto the action of POCl₃ to obtain a compound of formula (III):

[0043] wherein R², n and R_(a) are as defined hereinabove, which isplaced:

[0044] in the presence of palladium-on-carbon to obtain a compound offormula (IV):

[0045] wherein R², n and R_(a) are as defined hereinabove,

[0046] or which is hydrogenated in the presence of palladium-on-carbonto yield a compound of formula (V):

[0047] wherein R², n and R_(a) are as defined hereinabove,

[0048] which compound of formula (V) is condensed with a compound offormula G-R′¹ wherein G represents a leaving group, such as a halogenatom, or a tert-butoxycarbonyl group, and R′¹ may have any of themeanings given for R¹ with the exception of a hydrogen atom, to yield acompound of formula (VI):

[0049] wherein R², R′¹, n and R_(a) are as defined hereinabove, thecompounds of formulae (III) to (VI) constituting the compounds offormula (VII):

[0050] wherein R², n and R_(a) are as defined hereinabove and X and therepresentation

are as defined for formula (I),

[0051] which is condensed with an amine of formula HNRR′ wherein R andR′ are as defined for formula (I) to obtain a compound of formula (I/a),a particular case of the compounds of formula (I):

[0052] wherein R², R, R′, X, n and the representation

are as defined hereinabove, or which compound of formula (VII) issubjected to a sequence of reactions conventional in organic chemistryto yield a compound of formula (VIII):

[0053] wherein R², X, n and the representation

are as defined hereinabove, which is:

[0054] either reacted with an acyl chloride ClCOR′ or the correspondingmixed or symmetric anhydride wherein R′ is as defined hereinabove toyield a compound of formula (I/b), a particular case of the compound offormula (I):

[0055] wherein R², R′, X, n and the representation

are as defined hereinabove, optionally followed by the action of acompound of formula R′_(a)-J wherein R′_(a) may have any of the meaningsof R′ and J represents a leaving group, such as a halogen atom or atosyl group, to obtain a compound of formula (I/c), a particular case ofthe compounds of formula (I):

[0056] wherein R², R′, R_(a)′, X, n and the representation

are as defined hereinabove,

[0057] or subjected to the action of a compound of formula (IX):

O═C═N—R′  (IX)

[0058] wherein R′ is as defined hereinabove, optionally followed by theaction of a compound of formula R′_(a)-J as defined hereinabove, toyield a compound of formula (I/d), a particular case of the compounds offormula (I):

[0059] wherein R², R, R′, n, X and the representation

are as defined hereinabove and R″ is as defined for formula (I), itbeing possible for the compounds of formulae (I/a) to (I/d) to besubjected to the action of a thionisation agent, such as Lawesson'sreagent for example, to yield a compound of formula (I/e), a particularcase of the compounds of formula (I):

[0060] wherein R², n and the representation

are as defined hereinabove and B represents a C(S)NRR′, N(R)C(S)R′ orN(R)C(S)NR′R″ group wherein R, R′ and R″ are as defined hereinabove,

[0061] the compounds (I/a) to (I/e) constituting the totality of thecompounds of formula (I), which compounds may be purified according to aconventional separation technique, are converted, if desired, intoaddition salts with a pharmaceutically acceptable acid or base, and areoptionally separated into the isomers according to a conventionalseparation technique.

[0062] The starting compounds (II) are either commercially available orare easily obtainable by the person skilled in the art by conventionalchemical reactions or by chemical reactions described in the literature.

[0063] The compounds of the invention and pharmaceutical compositionscontaining them prove to be useful in the treatment of disorders of themelatoninergic system.

[0064] A pharmacological study of the compounds of the invention has infact demonstrated that they are non-toxic, have a high affinity formelatonin receptors and have substantial activity in respect of thecentral nervous system and in respect of microcirculation, enabling itto be established that the products of the invention are useful in thetreatment of stress, sleep disorders, anxiety, severe depression,seasonal affective disorders, cardiovascular pathologies, pathologies ofthe digestive system, insomnia and fatigue due to jetlag, schizophrenia,panic attacks, melancholia, appetite disorders, obesity, insomnia, pain,psychotic disorders, epilepsy, diabetes, Parkinson's disease, seniledementia, various disorders associated with normal or pathologicalageing, migraine, memory loss, Alzheimer's disease, and in cerebralcirculation disorders. In another field of activity, it appears that theproducts of the invention can be used in the treatment of sexualdysfunction, that they have ovulation-inhibiting and immunomodulatingproperties and that they lend themselves to use in the treatment ofcancers.

[0065] The compounds will preferably be used in the treatment of severedepression, seasonal affective disorders, sleep disorders,cardiovascular pathologies, insomnia and fatigue due to jetlag, appetitedisorders and obesity.

[0066] For example, the compounds will be used in the treatment ofseasonal affective disorders and sleep disorders.

[0067] The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I) on its own or incombination with one or more pharmaceutically acceptable excipients.

[0068] Amongst the pharmaceutical compositions according to theinvention there may be mentioned more especially those which aresuitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal,perlingual, ocular or respiratory administration, especially tablets ordragées, sublingual tablets, sachets, paquets, gelatin capsules,glossettes, lozenges, suppositories, creams, ointments, dermal gels anddrinkable or injectable ampoules.

[0069] The dosage varies according to the sex, age and weight of thepatient, the administration route, the nature of the therapeuticindication or any associated treatments, and ranges from 0.01 mg to 1 gper 24 hours in one or more administrations.

[0070] The following Examples illustrate the invention and do not limitit in any way. The following Preparations result in compounds of theinvention or in synthesis intermediates for use in the preparation ofcompounds of the invention.

Preparation 1: Ethyl 4-(6-methoxy-3,4-dihydro-4-isoquinolinyl)butanoatehydrochloride Step A: Ethyl 5-cyano-5-(3-methoxyphenyl)pentanoate

[0071] Two grams of (3-methoxyphenyl)acetonitrile and 1.5 ml of ethyl4-bromobutyrate are dissolved in 50 ml of dimethylformamide at 0° C. Sixhundred milligrams of 60% sodium hydride (600 mg; 15 mmol) areprogressively added to the solution. The reaction mixture is stirred atambient temperature for 4 hours, taken up in 100 ml of acidic water andextracted with ether. The organic phase is then dried over magnesiumsulphate, filtered and evaporated under reduced pressure. The oilobtained is purified on a column (eluant:ether/cyclohexane 4/6) to yieldthe title product in the form of a yellow oil.

Step B: Ethyl 6-amino-5-(3-methoxyphenyl)hexanoate hydrochloride

[0072] The compound obtained in Step A (11.2 g; 43 mmol), dissolvedbeforehand in 150 ml of ethanol, is poured into an autoclave, and thenRaney nickel is added (10% by weight). The mixture is then placed underhydrogen pressure (10 bars) and heated at 50° C. for 48 hours withstirring. After removing the Raney nickel by filtration, the organicphase is evaporated under reduced pressure. The residue obtained istaken up in ether, HCl_((g)) is bubbled into the solution, which is thenstirred until precipitation occurs. The precipitate obtained is thensuction-filtered off and recrystallised from toluene, and the titleproduct is obtained in the form of a white solid.

[0073] Melting point: 104-106° C.

Step C: Ethyl 6-(formylamino)-5-(3-methoxyphenyl)hexanoate

[0074] The amine obtained in Step B, in the form of a base (6.4 g; 27mmol), is dissolved in 60 ml of ethyl formate. The reaction mixture isheated at reflux for 6 hours with stirring and then evaporated underreduced pressure. The residue obtained is taken up in ether. The organicphase is then washed in succession with acidic water (1N HCl), water,and a 10% hydrogen carbonate solution, subsequently dried over magnesiumsulphate, filtered and evaporated under reduced pressure to yield thetitle product in the form of a yellow oil.

Step D: Ethyl 4-(6-methoxy-3,4-dihydro-4-isoquinolinyl)butanoatehydrochloride

[0075] The formaldehyde obtained in Step C (6.8 g; 23 mmol) is dissolvedin 100 ml of acetonitrile, then the reaction mixture is heated toapproximately 60° C. Phosphorus oxychloride (7 ml) is added to thesolution, which is heated at reflux for 6 hours with stirring and thenevaporated under reduced pressure. The residue obtained is taken uptwice in ethanol and evaporated under reduced pressure, and is thentaken up in water. The aqueous phase is washed with dichloromethane andthen rendered alkaline with a saturated sodium hydrogen carbonatesolution and extracted with dichloromethane. The organic phase is driedover magnesium sulphate, filtered and evaporated under reduced pressure.The oil obtained is taken un in ether saturated with HCl_((g)) and thenevaporated under reduced pressure. The residue is taken up in toluene inthe heated state and is stirred until precipitation occurs. Theprecipitate obtained is then suction-filtered off and the title productis obtained in the form of a white solid.

[0076] Melting point: 97-99° C.

Preparation 2: tert-Butyl4-(2-aminoethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylateStep A: Methyl cyano(3-methoxyphenyl)acetate

[0077] Twenty five grams of (3-methoxyphenyl)acetonitrile are dissolvedin 200 ml of anhydrous THF in an Erlermeyer ground-necked flask. 60%sodium hydride (8.88 g; 0.37 mol) is added to the solution and thereaction mixture is heated at reflux for 30 minutes with stirring.Dimethyl carbonate (58 ml; 0.6814 mol) is then added dropwise in thecourse of half an hour and the reaction mixture is subsequently heatedat reflux for 2 hours with stirring. The reaction mixture is poured intocold and slightly acidic water. The aqueous phase is extracted withether, and then the ethereal phase is washed with water before beingevaporated. A solution of potassium carbonate (47.15 g; 0.34 mol ) isadded to the oil obtained above. After stirring, the mixture is washedwith ether. The ethereal phase obtained is rewashed with a solution ofpotassium carbonate (12.02 g; 0.08 mol). The two aqueous phases arecombined, immediately acidified, and extracted with ether. The organicphase so obtained is washed with a 10% sodium hydrogen carbonatesolution, dried over magnesium sulphate and evaporated under reducedpressure to yield the title product in the form of an orangey yellowoil.

Step B: Methyl 3-amino-2-(3-methoxyphenyl)propanoate hydrochloride

[0078] The compound obtained in Step A (34.32 g; 0.1672 mol) isdissolved in 150 ml of methanol. The solution is poured into anautoclave and then 50 ml of chloroform and platinium oxide (10% byweight) are added to the solution. The autoclave is placed underhydrogen pressure (60 bars) at ambient temperature and stirredmagnetically for 24 hours. After removal of the catalyst by filtration,the solution is evaporated under reduced pressure. The oil obtained istaken up in ether. The precipitate formed is suction-filtered off andrecrystallised from acetonitrile to yield the title product in the formof a white solid.

[0079] Melting point: 170-172° C.

Step C: Methyl 3-(formylamino)-2-(3-methoxyphenyl)propanoate

[0080] The compound obtained in Step B (20.25 g; 0.08 mol), in the formof a base, is dissolved in 130 ml of ethyl formate (1.81 mol). Thereaction mixture is heated at reflux for 6 hours and then evaporatedunder reduced pressure. The oil obtained is taken up in ethyl acetate.The organic phase is washed with basic water (NaHCO₃), dried overmagnesium sulphate, filtered and evaporated to yield the title productin the form of a yellow oil.

Step D: Methyl 6-methoxy-3,4-dihydro-4-isoquinolinecarboxylatehydrochloride

[0081] The compound obtained in Step C (8.03 g; 0.03 mol) is dissolvedin 100 ml of acetonitrile, and then the reaction mixture is heated toapproximately 60° C. Phosphorus oxychloride (16 ml; 0.17 mol) is addedto the solution, which is then heated at reflux for 6 hours withstirring and subsequently evaporated under reduced pressure. The residueobtained is taken up twice with methanol and evaporated under reducedpressure, and then taken up in a minimum of acetone. The precipitateformed is then suction-filtered off to yield the title product in theform of a white solid.

[0082] Melting point : 212-215° C.

Step E: Methyl 6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinecarboxylatehydrochloride

[0083] The compound obtained in Step D (9.21 g), in the form of a base,is dissolved in 150 ml of methanol and then palladium-on-carbon (900 mg)is added to the solution. The reaction mixture is stirred at ambienttemperature under hydrogen for 4 hours. After removal of thepalladium-on-carbon by filtration, the organic phase is evaporated underreduced pressure. The oil obtained is taken up in ether saturated withHCl. The precipitate formed is suction-filtered off and recrystallisedfrom acetonitrile to yield the title product in the form of a whitesolid.

[0084] Melting point: 191-193° C.

Step F: tert-Butyl 4-methyl6-methoxy-3,4-dihydro-2,4(1H)-isoquinoline-dicarboxylate

[0085] The compound obtained in Step E (4.02 g; 15 mmol) is suspended in100 ml of dichloromethane and then triethylamine (6.6 ml) is added. Whendissolution is complete, di-tert-butyl dicarbonate (4 g; 18 mmol) isadded and the reaction mixture is stirred at ambient temperature for 30minutes. The solution is poured into 100 ml of water and the excess oftriethylamine is neutralised with acidic water (0.1N HCl). Afterseparation, the aqueous phase is extracted with dichloromethane and thecombined organic solutions are dried over magnesium sulphate, filteredand evaporated under reduced pressure. The title product is purified bychromatography on silica gel.

[0086] Colourless oil.

[0087] Step G: tert-Butyl4-(hydroxymethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinoline-carboxylate

[0088] Lithium aluminium hydride (5.62 g; 148 mmol) is suspended in 50ml of anhydrous tetrahydrofuran. A solution of the compound obtained inStep F (11.9 g; 37 mmol), dissolved beforehand in 50 ml of anhydroustetrahydrofuran, is then added dropwise. The reaction mixture is thenstirred at ambient temperature for 2 hours. A minimum of sodiumhydroxide solution (2N NaOH) is added to the reaction mixture until theevolution of gas has ceased in order to form the precipitates of lithiumand aluminium hydroxides. The precipitates are then filtered off andwashed with tetrahydrofuran. The organic phase is evaporated underreduced pressure. The title compound is purified by chromatography onsilica gel.

[0089] Clear yellow oil.

Step H: tert-Butyl6-methoxy-4-{[(methylsulphonyl)oxy]methyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0090] The compound obtained in Step G (10.5 g; 36 mmol) is dissolved in150 ml of dichloromethane and then triethylamine (8.5 ml) is added. Thesolution is cooled to 0° C. and methanesulphonyl choride (4.8 ml; 62mmol) is added dropwise. The reaction mixture is stirred at ambienttemperature for 2 hours and then poured into 150 ml of water. Thesolution is extracted with dichloromethane, dried over magnesiumsulphate, filtered and evaporated under reduced pressure. The titlecompound is purified by chromatography on silica gel.

[0091] Yellow oil.

Step I: tert-Butyl4-(cyanomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0092] Potassium cyanide (5.52 g; 85 mmol) is suspended in 50 ml of DMSOand the solution is heated to 80° C. The compound obtained in Step H(6.3 g; 17 mmol), dissolved beforehand in 50 ml of DMSO, isprogressively added to the preceding solution, and then the reactionmixture is heated again at 80° C. for 30 minutes. The solution is pouredinto 150 ml of water and extracted three times with dichloromethane. Theorganic phase is then dried over magnesium sulphate, filtered andevaporated. The dark red oil obtained is purified by chromatography onsilica gel (eluant:cyclohexane with the progressive addition of ethylacetate until the proportions 8/2 are reached) and the solid obtained isrecrystallised from cyclohexane to yield the title product in the formof a white solid.

[0093] Melting point: 75-77° C.

Step J: tert-Butyl4-(2-aminoethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0094] The compound obtained in Step I (6.3 g; 21 mmol) is dissolved in150 ml of methanol saturated with NH_(3(g)). The solution is poured intoan autoclave and Raney nickel (600 mg) is added. The reaction mixture isthen stirred at 60° C. and under a hydrogen pressure of 50 bars for 6hours. After removal of the catalyst by filtration, the solution isevaporated under reduced pressure and the title compound is obtained inthe form of a colourless oil.

Preparation 3: (6-Methoxy4-isoquinolinyl)acetonitrile hydrochloride StepA: Methyl 6-methoxy-4-isoquinolinecarboxylate hydrochloride

[0095] The compound obtained in Step D of Preparation 2 (1.56 g; 0.006mol), in the form of a base, is dissolved in 10 ml ofdecahydronaphthalene and then activated palladium-on-carbon is added(10% by weight). The reaction mixture is heated at 130° C. for 24 hourswith stirring. The catalyst is filtered off in the heated state andwashed with ethyl acetate. After evaporation under reduced pressure, theoil obtained is taken up in an ethereal solution saturated withHCl_((g)). The precipitate formed is suction-filtered off andrecrystallised from acetonitrile to yield the title product in the formof a white solid.

[0096] Melting point: 178-180° C.

Step B: (6-Methoxy-4-isoquinolinyl)methanol hydrochloride

[0097] The compound obtained in Step A (0.395 g; 0.0015 mol), in theform of a base, is dissolved in 200 ml of ether. Lithium aluminiumhydride (0.14 g; 0.004 mol) is then progressively added while coolingthe flask in ice. The reaction mixture is stirred at ambient temperaturefor one week. A minimum of 30% sodium hydroxide solution (a few drops)is added to the reaction mixture to form the precipitates of lithium andaluminium hydroxides. The precipitates are then filtered off and washedwith ethyl acetate. The organic phase is dried over magnesium sulphate,filtered and evaporated under reduced pressure. The oil obtained istaken up in ether saturated with HCl_((g)). The precipitate formed issuction-filtered off and recrystallised from acetonitrile to yield thetitle product in the form of a white solid.

[0098] Melting point: 250-252° C.

Step C: 4-(Chloromethyl)-6-methoxyisoquinoline

[0099] The hydrochloride of the compound obtained in Step B (1.09 g;0.005 mol) is suspended in 50 ml of chloroform. Thionyl chloride (2.80ml; 0.04 mol) is added and then the reaction mixture is heated at refluxfor 24 hours with stirring. After evaporation under reduced pressure,the residue obtained is taken up in ethyl ether. The precipitate formedis suction-filtered off and recrystallised from acetonitrile to yieldthe title compound in the form of a white solid.

[0100] Melting point: 256-257° C.

Step D: (6-Methoxy-4-isoquinolinyl)acetonitrile hydrochloride

[0101] The hydrochloride of the compound obtained in Step C (0.60 g;0.0024 mol) is dissolved in 10 ml of a saturated aqueous potassiumcarbonate solution and 40 ml of dichloromethane. Tetrabutylammoniumbromide (2 g; 0.006 mol) and potassium cyanide (0.80 g; 0.012 mol) arethen added to the preceding solution. The reaction mixture is stirred atambient temperature for 24 hours. The solution is extracted withdichloromethane, and the organic phase is washed with water, dried overmagnesium sulphate, filtered and evaporated. The oil obtained is takenup in acetone and in ether saturated with HCl_((g)). The precipitateformed is suction-filtered off and recrystallised fromtoluene/cyclohexane, 5/5, to yield the title compound in the form of ayellow solid.

[0102] Melting point : 114-115° C.

Preparation 4: tert-Butyl4-(aminomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate StepA: tert-Butyl6-methoxy-4-{[(methylsulphonyl)oxy]methyl}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0103] The procedure is as in Steps A to H of Preparation 2.

Step B: tert-Butyl4-(azidomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0104] Sodium azide (1.12 g) is suspended in 40 ml of DMF and thesolution is heated to 80° C. The compound obtained in Step A (1.6 g),dissolved beforehand in 10 ml of DMF, is progressively added to thepreceding solution, and then the reaction mixture is heated again at 80°C. for from 2 to 3 hours.

[0105] The solution is poured into 150 ml of water and extracted threetimes with ethyl acetate. The organic phase is then dried over magnesiumsulphate, filtered and evaporated. The dark red oil obtained is purifiedby chromatography on silica gel (eluant:cyclohexane with the progressiveaddition of ethyl acetate until the proportions 5/5 are reacehd) toyield the title product in the form of a colourless oil.

Step C: tert-Butyl4-(aminomethyl)-6-methoxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate

[0106] The compound obtained in Step B (1.14 g) is dissolved in 100 mlof methanol and then palladium-on-carbon (120 mg) is added to thesolution. The reaction mixture is stirred at ambient temperature andunder hydrogen for 3 hours.

[0107] After removal of the palladium-on-carbon by filtration, theorganic phase is evaporated under reduced pressure. The residue obtainedis purified by chromatography on silica gel (eluant:cyclohexane with theprogressive addition of ethyl acetate until the proportions 5/5 arereached) to yield the title product in the form of a colourless oil.

EXAMPLE 1 4-(6-methoxy-3,4-dihydro-4-isoquinolinyl)-N-methylbutanamide

[0108] The compound obtained in Preparation 1 (41 mmol), in the form ofa base, is dissolved in 10 ml of ethanol. 60 ml of aqueous methylamineare added and the reaction mixture is stirred at ambient temperature for12 hours. After evaporation under reduced pressure, the filtrate istaken up in 50 ml of water and extracted with dichloromethane. Theorganic phase is washed with water, dried over magnesium sulphate,filtered and evaporated under reduced pressure. The title product isobtained after chromatography of the resulting oil on silica gel.

[0109] Yellow oil.

EXAMPLE 24-(6-Methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)-N-methylbutanamide

[0110] The compound obtained in Example 1 (54 mmol), in the form of abase, is dissolved in 50 ml of methanol and then palladium-on-carbon(150 mg) is added to the solution. The reaction mixture is stirred atambient temperature and under hydrogen for 4 hours. After removal of thepalladium-on-carbon by filtration, the organic phase is evaporated underreduced pressure. The oil obtained is purified by chromatography onsilica gel to yield the title product in the form of a yellow oil.

EXAMPLE 3 4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide Step A: Ethyl4-(6-methoxy-4-isoquinolinyl)butanoate hydrochloride

[0111] The compound obtained in Preparation 1 (1.6 g; 5 mmol) isdissolved, with the application of heat, in 20 ml of toluene containingtriethylamine (0.9 ml) and absolute ethanol (2 ml). Palladium-on-carbon(300 mg) is added to the reaction mixture, which is then heated atreflux for 24 hours with stirring. After removal of thepalladium-on-carbon by filtration, the organic phase is evaporated underreduced pressure. The residue obtained is purified by chromatography onsilica gel (eluant:dichloromethane with the progressive addition ofmethanol). The oil obtained is converted to hydrochloride form and thenthe precipitate formed is recrystallised from acetonitrile.

[0112] Melting point: 190-192° C.

Step B: 4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide

[0113] The compound obtained in Step A (2.2 g; 7 mmol) is dissolved in30 ml of methylamine (40% in water) and the mixture is heated at refluxfor 3 hours with stirring. The reaction mixture is taken up in 50 ml ofwater and extracted with ether. The organic phase is washed with water,dried over magnesium sulphate, filtered and evaporated under reducedpressure. The oil obtained is purified by chromatography on silica gel(eluant:dichloromethane with the progressive addition of methanol). Theoil obtained is evaporated under reduced pressure and the precipitate soformed is recrystallised from toluene to yield the title product in theform of a white solid.

[0114] Melting point: 117-119° C.

[0115] Elemental Microanalysis: C % H % N % calculated 69.74 7.02 10.84found 69.64 7.22 10.83

EXAMPLE 4N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetamidehydrochloride

[0116] The compound obtained in Step I of Preparation 2 (6 g; 20 mmol)is dissolved in 100 ml of acetic anhydride and then the solution ispoured into an autoclave. Raney nickel (600 mg) is then added to thesolution and the reaction mixture is stirred at 60° C. and under ahydrogen pressure of 50 bars for 6 hours. After removal of the catalystby filtration, the solution is evaporated under reduced pressure. Theorange residue obtained is taken up in a 10% sodium hydroxide solutionand stirred for 15 minutes, and then extracted with ethyl acetate (3times). The organic phase is washed once with water, dried overmagnesium sulphate, filtered and evaporated under reduced pressure. Theoil obtained is taken up in 50 ml of methanol. Hydrogen chloride gas isbubbled into the solution, which is then stirred for 24 hours with aCaCl₂ guard. The solution is evaporated under reduced pressure and theprecipitate so obtained is recrystallised from acetonitrile to yield thetitle product in the form of a white solid.

[0117] Melting point: 182-184° C.

EXAMPLE 5N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]propanamidehydrochloride

[0118] The compound obtained in Preparation 2 and 2 equivalents ofpotassium carbonate are dissolved in a 3/2 ethyl acetate/water mixture.Propanoyl chloride (2 equivalents) is then added dropwise to thesolution. The reaction mixture is stirred at ambient temperature for onehour. After separation of the phases, the organic phase is washed withwater, dried over magnesium sulphate, filtered and evaporated underreduced pressure. The oil obtained is purified by chromatography onsilica gel (eluant ethyl acetate/cyclohexane 5/5). The oil obtained istaken up in methanol. Hydrogen chloride gas is bubbled into thesolution, which is then stirred for 24 hours with a CaCl₂ guard. Thesolution is evaporated under reduced pressure and the title compound isobtained in the form of a white solid.

[0119] Melting point: 161-163° C.

EXAMPLE 6N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]butanamidehydrochloride

[0120] The title compound is obtained by the same procedure as inExample 5, with the replacement of propanoyl chloride by butanoylchloride.

[0121] Very hygroscopic white solid.

EXAMPLE 7N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]cyclopropane-carboxamidehydrochloride

[0122] The title compound is obtained by the same procedure as inExample 5, with the replacement of propanoyl chloride bycyclopropylcarboxylic acid chloride.

[0123] White solid. Melting point: 215-217° C.

EXAMPLE 8N-[2-(6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]cyclobutane-carboxamidehydrochloride

[0124] The title compound is obtained by the same procedure as inExample 5, with the replacement of propanoyl chloride bycyclobutylcarboxylic acid chloride.

[0125] White solid. Melting point: 130-132° C.

EXAMPLE 9 N-[2-(6-methoxy-4-isoquinolinyl)ethyl]acetamide hydrochloride

[0126] The compound obtained in Preparation 3 (0.30 g; 0.0015 mol), inthe form of a base, dissolved beforehand in 10 ml of acetic anhydride,is poured into an autoclave and then Raney nickel is added (10% byweight). The mixture is then placed under hydrogen pressure (60 bars)and heated at 60° C. for 6 hours with stirring. After removal of theRaney nickel by filtration, the organic phase is taken up in 10% sodiumhydroxide solution at ambient temperature and stirred magnetically for15 minutes. The solution is extracted with ethyl acetate, the organicphase is washed with brine, dried over magnesium sulphate, filtered andevaporated under reduced pressure. The oil obtained is purified on acolumn (eluant dichloromethane with the progressive addition of methanoluntil the proportions 9/1 are reached). The purified oil is taken up inether saturated with HCl_((g)). The precipitate formed issuction-filtered off and recrystallised from ethanol to yield the titleproduct in the form of a white solid.

[0127] Melting point: 212-214° C.

EXAMPLE 10 N-[2-(6methoxy-4-isoquinolinyl)ethyl]propanamidehydrochloride

[0128] The compound of Example 5 is dissolved in a minimum of methanolwith the application of heat and then diluted with toluene. 1.5equivalents of triethylamine are then added to the solution, and thereaction mixture is subsequently heated at reflux in the presence ofpalladium-on-carbon (10% by weight) for 3 hours. After removal of thecatalyst by filtration, the solution is evaporated under reducedpressure. The oil obtained is purified by chromatography on silica gel(eluant dichlormethane/methanol 9/1). The purified oil is taken up inether saturated with HCl_((g)) and stirred until a precipitate isobtained. The precipitate so formed is suction-filtered off and placedunder vacuum in a dessicator. The title product is obtained in the formof a white solid.

[0129] Melting point: 233-235° C.

EXAMPLE 11 N-[2-(6-methoxy-4-isoquinolinyl)ethyl]butanamidehydrochloride

[0130] The title compound is obtained according to the same procedure asin Example 10 starting from the compound obtained in Example 6.

[0131] Melting point: 195-197° C.

EXAMPLE 12 N-[2-(6-methoxy-4-isoquinolinyl)ethyl]cyclopropanecarboxamidehydrochloride

[0132] The title compound is obtained according to the same procedure asin Example 10 starting from the compound obtained in Example 7.

[0133] Melting point: 226-228° C.

EXAMPLE 13N-[2-(6methoxy-2-phenyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]-acetamidehydrochloride

[0134] The compound obtained in Example 4 (460 mg; 1.8 mmol), in theform of a base, is suspended in 30 ml of dichloromethane.Triphenylbismuth (900 mg; 2 mmol) and copper acetate Cu(OAc)₂ (190 mg;0.95 mmol) are then added. The reaction mixture is placed under argonand stirred magnetically for 18 hours at ambient temperature. Themixture is filtered, taken up in water and extracted with ethyl acetate.The organic phase is dried over magnesium sulphate, filtered andevaporated under reduced pressure. The residue obtained is purified bychromatography on silica gel (eluant ethyl acetate/cyclohexane 2/8). Thepurified oil is taken up in ether saturated with HCl_((g)) and stirreduntil a precipitate is obtained, which precipitate is thensuction-filtered off and placed under a vacuum in a dessicator to yieldthe title product in the form of a white solid.

[0135] Melting point : 83-85° C.

EXAMPLE 14N-[2-(2-benzyl-6methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]-acetamide

[0136] The compound obtained in Example 4 (740 mg; 2.5 mmol) andpotassium carbonate (720 mg; 5 mmol) are suspended in 20 ml of DMF, andthen benzyl bromide (0.37 ml; 3 mmol) is added to the solution. Thereaction mixture is heated at 125° C. for 4 hours with stirring. Thesolution is poured into 50 ml of water, acidified with 6N HCl and washedwith ethyl acetate. The aqueous phase is then rendered alkaline withpotassium carbonate and extracted with dichloromethane. The organicphase is dried over magnesium sulphate, filtered and evaporated underreduced pressure. The residue so obtained is purified by chromatographyon silica gel (eluant: dichloromethane with the progressive addition ofmethanol until the proportions 9/1 are reached). The purified oilprecipitates. The precipitate so formed is recrystallised from a 7/3toluene/cyclohexane mixture to yield the title product in the form of awhite solid.

[0137] Melting point: 123-125° C.

EXAMPLE 15N-{2-[2-(3-formylphenyl)-6-methoxy-1,2,3,4-tetrahydro-4-iso-quinolinyl]ethyl}acetamide

[0138] Copper acetate Cu(OAc)₂ (960 mg; 5 mmol) and triethylamine (1.5ml; 10.5 mmol) are suspended in 60 ml of dichloromethane. The compoundof Example 4 (1 g; 3.5 mmol), 3-formylphenylboronic acid (1.05 g; 7mmol) and molecular sieve are then added in succession and progressivelyto the solution. The reaction mixture is stirred at ambient temperaturefor 2 hours. The mixture is filtered, washed with water, dried overmagnesium sulphate, filtered and evaporated under reduced pressure. Theresidue obtained is purified by chromatography on silica gel(eluant:dichloromethane with the progressive addition of methanol untilthe proportions 9/1 are reached) to yield the title product in the formof a yellow oil.

EXAMPLE 16N-[2-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]-acetamidehydrochloride

[0139] Formic acid (0.55 ml) and 37% formaldehyde (0.6 ml) are added at0° C. to the compound obtained in Example 4 (1.8 g; 7.2 mmol) in theform of a base. The reaction mixture is heated at 80° C. for 24 hourswith stirring. After having cooled the reaction mixture to 0° C., 10 mlof 6N HCl are added. The mixture is then washed with ether, renderedalkaline with 2N NaOH and extracted with ether. The organic phase isdried over magnesium sulphate, filtered and evaporated under reducedpressure. The yellow oil so obtained is purified by chromatography onsilica gel (eluant: dichloromethane with the progressive addition ofmethanol until the proportions 9/1 are reached). The purified oil istaken up in ether saturated with HCl_((g)) and stirred until aprecipitate is obtained, which precipitate is then suction-filtered offand placed under a vacuum in a dessicator to yield the title product inthe form of a very hygroscopic white solid.

[0140] Melting point: 59-61° C.

EXAMPLE 17N-{2-[2-(Cyclopropylmethyl)-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl]ethyl}acetamidehydrochloride

[0141] The compound obtained in Example 4 (1.03 g) and potassiumcarbonate (1.25 g) are suspended in 50 ml of acetone. The solution isstirred at ambient temperature for 10 minutes, and thenmethylcyclopropane bromide (0.36 ml) is added to the solution. Thereaction mixture is stirred at ambient temperature for 12 hours.

[0142] The potassium carbonate is filtered off and the recoveredsolution is evaporated. The residue is taken up in water and the aqueousphase is extracted with ether. The organic phase is dried over magnesiumsulphate, filtered and evaporated under reduced pressure. The residue soobtained is purified by chromatography on silica gel(eluant:dichloromethane with the progressive addition of methanol untilthe proportions 9/1 are reached).

[0143] The purified oil is taken up in ether saturated with HCl_((g))and stirred until a precipitate is obtained, which precipitate is thensuction-filtered off and placed under a vacuum in a dessicator to yieldthe title product in the form of a hygroscopic white solid.

[0144] Melting point: <50° C.

EXAMPLE 18N-[(6-Methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)methyl]acetamidehydrochloride

[0145] The compound obtained in Preparation 4 (0.77 g) and potassiumcarbonate (1.8 g) are dissolved in 50 ml of a 1/1 dichloromethane/watermixture. Acetyl chloride (0.47 ml) is then added dropwise to thesolution. The reaction mixture is stirred at ambient temperature for 2hours.

[0146] After separation of the phases, the organic phase is washed withwater, dried over magnesium sulphate, filtered and evaporated underreduced pressure.

[0147] The oil obtained is taken up in methanol. Hydrogen chloride gasis bubbled into the solution, which is then stirred with a CaCl₂ guardfor 24 hours, the deprotection time. The solution is evaporated underreduced pressure and the precipitate obtained is recrystallised fromacetonitrile to yield the title product in the form of a white solid.

[0148] Melting point: 246-248° C.

Pharmacological Study EXAMPLE A Acute Toxicity Study

[0149] Acute toxicity was evaluated after oral administration to groupseach comprising 8 mice (26±2 grams). The animals were observed atregular intervals during the course of the first day, and daily for thetwo weeks following treatment. The LD₅₀ (the dose that causes the deathof 50% of the animals) was evaluated and demonstrated the low toxicityof the compounds of the invention.

EXAMPLE B Forced Swimming Test

[0150] The compounds of the invention are tested in a behavioural model,the forced swimming test.

[0151] The apparatus is a Plexiglas cylinder filled with water. Theanimals are tested individually for a session of 6 minutes. At thebeginning of each test, the animal is placed in the centre of thecylinder. The period of immobility is recorded. Each animal is judged tobe immobile when it ceases to struggle and remains immobile on thesurface of the water only making movements that allow it to keep itshead out of the water.

[0152] After administration 40 minutes before the beginning of the test,the compounds of the invention significantly reduce the period ofimmobility, demonstrating the anti-depressant activity of the compoundsof the invention. In particular, the compound of Example 9, administeredat 2.5 mg/kg per os, causes the duration of immobility to be reducedfrom 102 seconds (control) to 57 seconds. The compound of Example 3,administered at 25 mg/kg per os, causes the duration of immobilisationto be reduced from 129 seconds (control) to 60 seconds.

EXAMPLE C Study of Binding to Melatonin Receptors MT₁ and MT₂

[0153] The MT₁ or MT₂ receptor binding experiments are carried out using2-[¹²⁵I]-iodomelatonin as reference radioligand. The radioactivityretained is determined using a liquid scintillation counter.

[0154] Competitive binding experiments are then carried out intriplicate using the various test compounds. A range of differentconcentrations is tested for each compound. The results enable thebinding affinities (K_(i)) of the compounds tested to be determined.

[0155] Thus, the K_(i) values found for the compounds of the inventionshow binding for one or the other of the receptor sub-types MT₁ or MT₂,those values being ≦10 μM.

[0156] In particular, the compound of Example 9 has a K_(i) (MT₁) of9.12×10⁻⁹M and a K_(i)(MT₂) of 2.16×10⁻⁹M; the compound of Example 3 hasa K_(i)(MT₁) of 3.8×10⁻⁹M and a K_(i)(MT₂) of 2.6×10⁻⁹M ; the compoundof Example 10 has a K_(i)(MT₁) of 4.26×10⁻⁹M and a K_(i)(MT₂) of1.14×10⁻⁹M.

EXAMPLE D Action of the Compounds of the Invention on the CircadianRhythms of Locomotive Activity of the Rat

[0157] The implication of melatonin in influencing the majority ofphysiological, biochemical and behavioural circadian rhythms byday/night alternation has made it possible to establish apharmacological model for research into melatoninergic ligands.

[0158] The effects of the compounds are tested in relation to numerousparameters and, in particular, in relation to the circadian rhythms oflocomotive activity, which are a reliable indicator of the activity ofthe endogenous circadian clock.

[0159] In this study, the effects of such compounds on a particularexperimental model, namely the rat placed in temporal isolation(permanent darkness), are evaluated.

[0160] Experimental Protocol

[0161] One-month-old male rats are subjected, as soon as they arrive atthe laboratory, to a light cycle of 12 hours of light per 24 hours (LD12:12).

[0162] After 2 to 3 weeks' adaptation, they are placed in cages fittedwith a wheel connected to a recording system in order to detect thephases of locomotive activity and thus monitor the nychthemeral (LD) orcircadian (DD) rhythms.

[0163] As soon as the rhythms recorded show a stable pattern in thelight cycle LD 12:12, the rats are placed in permanent darkness (DD).

[0164] Two to three weeks later, when the free course (rhythm reflectingthat of the endogenous clock) is clearly established, the rats are givena daily administration of the compound to be tested.

[0165] The observations are made by means of visualisation of therhythms of activity:

[0166] influence of the light rhythm on the rhythms of activity,

[0167] disappearance of the influence on the rhythms in permanentdarkness,

[0168] influence by the daily administration of the compound; transitoryor durable effect.

[0169] A software package makes it possible:

[0170] to measure the duration and intensity of the activity, the periodof the rhythm of the animals during free course and during treatment,

[0171] to demonstrate by spectral analysis the existence of circadianand non-circadian (for example ultradian) components, where present.

[0172] Results

[0173] The compounds of the invention clearly appear to have a powerfulaction on the circadian rhythm via the melatoninergic system.

EXAMPLE E Light/Dark Cages Test

[0174] The compounds of the invention are tested in a behavioural model,the light/dark cages test, which enables the anxiolytic activity of thecompounds to be revealed.

[0175] The equipment comprises two polyvinyl boxes covered withPlexiglas. One of the boxes is in darkness. A lamp is placed above theother box, yielding a light intensity of approximately 4000 lux at thecentre of the box. An opaque plastics tunnel separates the light boxfrom the dark box. The animals are tested individually for a session of5 minutes. The floor of each box is cleaned between each session. At thestart of each test, the mouse is placed in the tunnel, facing the darkbox. The time spent by the mouse in the illuminated box and the numberof passages through the tunnel are recorded after the first entry intothe dark box.

[0176] After administration of the compounds 30 minutes before the startof the test, the compounds of the invention significantly increase thetime spent in the illuminated cage and the number of passages throughthe tunnel, which demonstrates the anxiolytic activity of the compoundsof the invention.

EXAMPLE F Activity of the Compounds of the Invention on the CaudalArtery of the Rat

[0177] The compounds of the invention were tested in vitro on the caudalartery of the rat. Melatoninergic receptors are present in thosevessels, thus providing a relevant pharmacological model for studyingmelatoninergic ligand activity. The stimulation of the receptors caninduce either vasoconstriction or dilation depending upon the arterialsegment studied.

[0178] Protocol

[0179] One-month-old rats are accustomed to a light/dark cycle of12h/12h during a period of 2 to 3 weeks.

[0180] After sacrifice, the caudal artery is isolated and maintained ina highly oxygenated medium. The arteries are then cannulated at bothends, suspended vertically in an organ chamber in a suitable medium andperfused via their proximal end. The pressure changes in the perfusionflow enable evaluation of the vasoconstrictive or vasodilatory effect ofthe compounds.

[0181] The activity of the compounds is evaluated on segments that havebeen pre-contracted by phenylephrine (1 μM). A concentration/responsecurve is determined non-cumulatively by the addition of a concentrationof the test compound to the pre-contracted segment. When the effectobserved reaches equilibrium, the medium is changed and the preparationis left for 20 minutes before the addition of the same concentration ofphenylephrine and a further concentration of the test compound.

[0182] Results

[0183] The compounds of the invention significantly modify the diameterof caudal arteries pre-constricted by phenylephrine.

EXAMPLE G Pharmaceutical Composition: Tablets

[0184] 1000 tablets each containing a dose of 5 mg of N-[2-(6-methoxy-4- 5 g isoquinolinyl)-ethyl]acetamide hydrochloride (Example 9) wheatstarch 20 g maize starch 20 g lactose 30 g magnesium stearate  2 gsilica  1 g hydroxypropyl cellulose  2 g

1. A compound selected from those of formula (I):

wherein: n is 1, 2 or 3, A represents

wherein: Z represents sulphur or oxygen, R and R″, which may beidentical or different, each represents hydrogen or linear or branched(C₁-C₆)alkyl, and R′ represents linear or branched (C₁-C₆)alkyl, linearor branched (C₂-C₆)alkenyl, linear or branched (C₂-C₆)alkynyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl in which the alkylmoiety is linear or branched, aryl, aryl-(C₁-C₆)alkyl in which the alkylmoiety is linear or branched, heteroaryl or heteroaryl(C₁-C₆)alkyl inwhich the alkyl moiety is linear or branched, X represents nitrogen orN—R¹ wherein R¹ represents hydrogen or linear or branched (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl in which the alkylmoiety is linear or branched, aryl, aroyl, aryl-(C₁-C₆)alkyl in whichthe alkyl moiety is linear or branched, heteroaryl, heteroaroyl orheteroaryl-(C₁-C₆)alkyl in which the alkyl moiety is linear or branched,R² represents linear or branched (C₁-C₆)alkoxy, (C₃-C₈)cycloalkyloxy or(C₃-C₈)cycloalkyl-(C₁-C₆)alkyloxy in which the alkyloxy moiety is linearor branched,

the representation denotes that the bond is single or double, with theproviso that the valency of the atoms is respected, its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base, it being understood that: “aryl” may be“phenyl” or “naphthyl”, each of those groups being optionallysubstituted by from one to three identical or different groups selectedfrom linear or branched (C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy,OH, COOH, alkoxycarbonyl in which the alkoxy moiety is linear orbranched, formyl, nitro, cyano, hydroxymethyl, amino (optionallysubstituted by one or two linear or branched (C₁-C₆)alkyl) and halogen,“heteroaryl” may be any mono- or bi-cyclic group that contains from 5 to10 ring members and may contain from 1 to 3 hetero atoms selected fromoxygen, sulphur and nitrogen, each of those groups being optionallypartially hydrogenated and optionally substituted by from one to threeidentical or different groups selected from linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)alkoxy, OH, COOH, alkoxycarbonylin which the alkoxy moiety is linear or branched, formyl, nitro, cyano,amino (optionally substituted by one or two linear or branched(C₁-C₆)alkyl), hydroxymethyl and halogen.
 2. A compound of claim 1wherein n is 2 and A represents —NHCOR′.
 3. A compound of claim 1wherein n is 3 and A represents CONHR′.
 4. A compound of claim 1 whereinR² represents methoxy.
 5. A compound of claim 1 wherein X representsnitrogen.
 6. A compound of claim 1 wherein X represents NPh or NBz.
 7. Acompound of claim 1 which isN-[2-(6-methoxy-4-isoquinolinyl)ethyl]acetamide, and its addition saltswith a pharmaceutically acceptable acid.
 8. A compound of claim 1 whichis N-[2-(6-methoxy-4-isoquinolinyl)ethyl]butanamide, and its additionsalts with a pharmaceutically acceptable acid.
 9. A compound of claim 1which is N-[2-(6-methoxy-4-isoquinolinyl)ethyl]propanamide, and itsaddition salts with a pharmaceutically acceptable acid.
 10. A compoundof claim 1 which isN-[2-(6-methoxy-4-isoquinolinyl)ethyl]cyclopropanecarboxamide, and itsaddition salts with a pharmaceutically acceptable acid.
 11. A compoundof claim 1 which is 4-(6-methoxy-4-isoquinolinyl)-N-methylbutanamide,and its addition salts with a pharmaceutically acceptable acid.
 12. Acompound of claim 1 which isN-[2-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetamide,and its addition salts with a pharmaceutically acceptable acid.
 13. Acompound of claim 1 which isN-[2-(2-benzyl-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl)ethyl]acetamide,and its addition salts with a pharmaceutically acceptable acid.
 14. Acompound of claim 1 which isN-{2-[2-(cyclopropylmethyl)-6-methoxy-1,2,3,4-tetrahydro-4-isoquinolinyl]ethyl}acetamide,and its addition salts with a pharmaceutically acceptable acid.
 15. Apharmaceutical composition useful for treating melatoninergic disorderscomprising as active principle an effective amount of a compound ofclaim 1 together with one or more pharmaceutically acceptable excipientsor vehicles.
 16. A pharmaceutical composition useful for treating sleepdisorders, stress, anxiety, seasonal affective disorders or severedepression, cardiovascular pathologies, pathologies of the digestivesystem, insomnia and fatigue due to jetlag, schizophrenia, panicattacks, melancholia, appetite disorders, obesity, insomnia, psychoticdisorders, epilepsy, diabetes, Parkinson's disease, senile dementia,various disorders associated with normal or pathological ageing,migraine, memory loss, Alzheimer's disease, cerebral circulationdisorders, and also in sexual dysfunction, as ovulation inhibitors,immunomodulators and cancers comprising as active principle an effectiveamount of a compound of claim 1 together with one or morepharmaceutically acceptable excipients or vehicles.
 17. A method fortreating a living animal body afflicted with disorders of themelatoninergic system comprising the step of administering to the animalbody an amount of a compound of claim 1 which is effective foralleviation of said disorder.
 18. A method for treating a living animalbody afflicted with a condition selected from sleep disorders, stress,anxiety, seasonal affective disorders, severe depression, cardiovascularpathologies, pathologies of the digestive system, insomnia and fatiguedue to jetlag, schizophrenia, panic attacks, melancholia, appetitedisorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes,Parkinson's disease, senile dementia, various disorders associated withnormal or pathological ageing, migraine, memory loss, Alzheimer'sdisease, cerebral circulation disorders, sexual dysfunction, asovulation inhibitors, immunomodulators, and cancer comprising the stepof administering to the animal body an amount of a compound of claim 1which is effective for alleviation of said condition.
 19. A method fortreating a living animal body afflicted with a condition treatable by anovulation inhibitor comprising the step of administering to the animalbody an amount of a compound of claim 1 which is effective foralleviation of said condition.
 20. A method for treating a living animalbody afflicted with a condition treatable by an immunomodulatorcomprising the step of administering to the animal body an amount of acompound of claim 1 which is effective for alleviation of saidcondition.